P1385: DISTINCT RATES OF ICANS BUT SIMILAR CYTOKINE SIGNATURES BETWEEN TWO CD19-CAR T CELL THERAPIES: LISOCABTAGENE MARALEUCEL AND AXICABTAGENE CILOLEUCEL
Authors: Yusuf Rasheed, Abu-Sayeef Mirza, Alexander Pine, Ramzi Hamouche, Etienne Leveille, George Goshua, Sean Gu, Yuxin Liu, Jennifer Vanoudenhove, Noffar Bar, Natalia Neparidze, Francine Foss, Lohith Gowda, Iris Isufi, Stephanie Halene, Alfred Lee, Stuart Seropian
Journal: HemaSphere (2023)

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Multiple Chimeric antigen receptor T-cell (CAR-T) products have been approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma. These products have varying rates of toxicity including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Predictive biomarkers and targeted treatment strategies are limited for ICANS. Aims: We compared longitudinal cytokine profiles during the development of ICANS in patients receiving two different CD19-directed CAR T-cell therapies. Methods: Between April – December 2022, 12 patients received CD19-CAR T-cell therapy and consented to the Yale School of Medicine hematologic disease tissue bank (HIC#1401013259). Two longitudinal cohorts were prospectively enrolled: patients who received (1) axicabtagene cileucel (axi-cel) for DLBCL refractory to 1-2 lines of therapy and (2) lisocabtagene maraleucel (liso-cel) for DLBCL refractory after two lines of therapy. For each patient, the first sample was collected prior to lymphodepleting chemotherapy on day -5 with subsequent samples collected on days 0 (prior to CAR T-cell infusion) and 1, 2, 3, and 7 (after CAR T-cell infusion). Proteomic profiling was performed at each timepoint using Eve Technologies (Calgary, Alberta, Canada) using the Human 71-Plex Discovery Assay measuring 71 total cytokines and chemokines. Statistical analysis was performed in GraphPad Prism (GraphPad Software, San Diego, CA) and R (R Core Team). Protein levels were compared between patients who those who did or did not develop ICANS, as well as between the two CAR-T cell products using Wilcoxon tests. P-values <0.05 were statistically significant. Results: Among 12 patients with DLBCL, 7 received axi-cel, 5 received liso-cel, median age was 68 years (range 45-84), 9 (75%), 11 (92%) were considered double-expressor, 3 (25%) had double or triple hit pathology, 6 (50%) had clinically bulky disease, and 9 (75%) required bridging chemotherapy. Six patients (50%) had any grade CRS with one patient from the liso-cel cohort having maximum grade 2 CRS, one patient from the axi-cel cohort having maximum grade 4 CRS, and 5 (42%) patients requiring tocilizumab treatment. Three patients (25%) had any grade ICANS: two out the 7 patients who received axi-cel (28%) developed grade 3-4 ICANS, and one out of the 5 patients who received liso-cel (20%) developed grade 1 ICANS. By 3 months of follow-up, the objective response rate was 83% (10/12). Among patients who had developed ICANS, the levels of Eotaxin-2 were significantly decreased on timepoints of days 1, 2 and 7. The levels of interleukin (IL)-15, IL-27, and IL-6 were similar between patients who developed ICANS compared to those who did not. Overall, the levels of cytokines at multiple timepoints were similar between patients who received axicabtagene ciloleucel compared to those who received lisocabtagene maraleucel. Summary/Conclusion: Our results suggest that between patients who received lisocabtagene maraleucel or axicabtagene ciloleucel and between patients who did or did not develop ICANS, cytokine signatures were similar. This is despite lisocabtagene maraleucel and axicabtagene ciloleucel having historically different toxicity profiles yet similar clinical outcomes. ICANs may involve multifactorial etiologies independent of any single serum cytokine. Further studies with larger cohorts of patients are needed to further elucidate the pathophysiology of ICANS. Figure: Cytokine Levels of Eotaxin-2, IL-6, IL-15, and IL-27 Across Days -5 to Day 7 after receiving axi-cel or liso-cel for patients with no ICANS (0) or any ICANS (1)Keywords: Cytokine, Diffuse large B cell lymphoma, CAR-T, Cellular therapy